|Publication number||US6252093 B1|
|Application number||US 09/679,831|
|Publication date||26 Jun 2001|
|Filing date||5 Oct 2000|
|Priority date||8 Aug 1996|
|Also published as||CA2262648A1, DE69728544D1, DE69728544T2, EP0918776A1, EP0918776B1, EP1454890A2, EP1454890A3, EP1454890A8, US5723632, US5856580, US6160184, US6469184, US6717017, US20010029303, US20030050495, WO1998005669A1|
|Publication number||09679831, 679831, US 6252093 B1, US 6252093B1, US-B1-6252093, US6252093 B1, US6252093B1|
|Inventors||Trevor C. McMorris|
|Original Assignee||The Regents Of The University Of California|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (23), Non-Patent Citations (53), Referenced by (4), Classifications (18), Legal Events (6)|
|External Links: USPTO, USPTO Assignment, Espacenet|
This is a divisional application of U.S. patent application Ser. No 09/242,091, filed on Jan. 6, 2000, now issued as U.S. Pat. No. 6,160,184, which is a U.S. National Stage Filing under 35 U.S.C. 371 of PCT/US 97/13644, filed Aug. 5, 1997, which is a continuation of U.S. patent application Ser. No. 08/689,461, filed Aug. 8, 1996, now issued as U.S. Pat. No. 5,723,632.
Natural products from plants and microorganisms have proven to be a major source of active anticancer agents and lead compounds for cancer chemotherapy. Mushrooms of the class Basidiomycetes are an exception. Although they occur widely and some are well known to contain a variety of highly poisonous substances, only Omphalolus illudens (jack o'lantern mushroom) is known to produce promising anticancer compounds. These are the sesquiterpenes illudin S and illudin M. The illudins are extremely cytotoxic compounds but have a low therapeutic index particularly in solid tumor systems. However, modification of their structures has yielded several analogs, which possess a greatly improved therapeutic index. Remarkable efficacy has been observed in tests on mouse xenografts of leukemias and various solid tumors.
First and second generation analogs, for example, dehydroilludin M and acylfulvene, have been described (WO 91/04754). A promising compound is a third generation analog hydroxymethylacylfulvene (HMAF). In tests with MV 522 metastatic lung carcinoma xenografts in nude mice, complete tumor regression was observed in all animals. HMAF also exhibited outstanding activity against breast (MX-1), colon (H-29) and skin cancers.
The structures of illudin S and illudin M were first published in 1963 (McMorris et al., J. Am. Chen Soc. 85:831 (1963)). Until recently only one total synthesis of these compounds had been reported (Matsumoto et al., Tetrahedron Lett. 1171 (1970)). This synthesis involved Michael addition of a cycylopropane intermediate to an appropriately substituted cyclopentenone. The resulting product was then transformed into an intermediate which could undergo aldol condensation to form illudin's six-membered ring. A number of further reactions were required to complete the synthesis.
Padwa et ale (J. Am. Chem. Soc. 116: 2667 (1994)), have published a synthetic approach to the illudin skeleton using a dipolar cycloaddition reaction of a cyclic carbonyl ylide dipole with cyclopentenone to construct the six-membered ring. Kinder and Bair (J. Org. Chem. 59:6955 (1994)), have also employed the Padwa methodology to synthesize illudin M. However, these syntheses are long and not well suited for making acylfulvenes on a large scale.
Thus, a continuing need exists for improved methods for synthesizing acylfulvenes.
The present invention provides a method of synthesizing compounds of formula (I):
wherein R and R′ are independently (C1-C4)alkyl, preferably methyl. According to the invention, a method is provided of synthesizing a compound of formula (V), a preferred intermediate in the synthesis of compounds of formula (I),:
comprising the steps of coupling a cyclopentanone of formula (II):
wherein R4 is —O—C(R9)2O(R9), wherein R9 is (C1-C4)alkyl, preferably methyl; with a cyclic carbonyl ylide dipole of formula (III):
to form a compound of formula (IV):
and treating compound (IV) with base to form a ketone of formula (V).
The present method further may further comprise the steps of dihydroxylating the ketone to yield a compound of formula (VI):
and treating the compound of formula (VI) with a removable 1,2-diol protecting reagent to yield an intermediate of formula (VII):
wherein X is a removable 1,2-diol protecting group. Protecting groups may be introduced by forming a cyclic acetal by treatment with an aldehyde or ketone such as acetone, formaldehyde, acetaldehyde or benzaldehyde. For example, an isopropylidene derivative (acetonide) may be introduced by reaction with acetone. Preferably, the isopropylidene group is introduced by acid-catalyzed exchange with 2,2dimethoxypropane.
The method further comprises the steps of treating compound (VII) with RMgCl, where R is (C1-C4)alkyl, to yield a Grignard product of formula VIII:
and cleaving the oxybridge to yield a diol of formula (IX):
The method further comprises the step of removing the diol protecting group to yield a tetraol of formula (X):
The tetraol is then converted to an orthoester of formula (XI):
wherein R″ is (C1-C3)alkyl; and the cis hydroxyls are eliminated to yield a dienone of formula (XII):
The method further comprises the steps of reducing the compound of formula (XII) to convert the ketone to an alcohol, under conditions which dehydrate the resulting alcohol to yield a fulvene of formula (XIII):
The fulvene of formula (XIII) is then oxidized to yield a compound of formula (I):
The present invention also provides a method of synthesizing a compound of formula (XVII):
wherein R1 is OH, R2 is H, and R′ is (C1-C4)allyl, preferably methyl.
According to the present invention, a method is provided of synthesizing a diketone of formula (XIII), a preferred intermediate in the synthesis of compounds of formula (XVII),:
comprising the steps of
(a) cleaving the oxybridge in the compound of formula (XIV):
to yield a diketone of formula (XIII).
The method further comprises the steps of
(b) protecting the hydroxyl group in the compound of formula (XIII) with a removable hydroxyl protecting group X; and
(c) introducing a double bond in the five-membered ring to yield a compound of the formula (XV):
wherein R′1 and R′2 together are keto; and
X is a removable hydroxyl protecting group. Removable hydroxyl protecting groups may be introduced by reaction with a suitable reagent, such as a reagent of the formula ((C1-C4)alkyl)3SiCl, including triethylsilyl (TES) chloride, trimethylsilyl (TMS) chloride, t-butyldimethylsilyl (TIBDMS) chloride, dimethyl (1,2,2-trimethylpropyl)silyl chloride, or tris(isopropyl)silyl; and methoxymethyl chloride, β-methoxyethoxymethyl chloride, and isobutylene.
The method further comprises the steps of
(d) reducing both keto groups to yield hydroxy groups under conditions that yield a compound of formula (XVI):
(e) eliminating the cyclopentenol hydroxyl group; and
(f) oxidizing the cyclohexanol hydroxyl group and removing hydroxyl protecting group X to yield a compound of formula (XVII):
wherein R1 is OH and R2 is H.
The method additionally comprises the step of
(g) following step (d), treating the alcohol with mesyl chloride in the presence of a base to produce a mesylate of the formula (XVIII):
wherein R″1 is —OX, R″2is absent and R is H.
The present invention further provides a method of synthesizing compounds of the formula (XXIII):
wherein R′1 and R′2 together are ethylenedioxy, and R′ is (C1-C4)alkyl, preferably methyl.
According to the present method, the carbonyl group of the compound of formula (XIII) is converted to an acetal group to yield a compound of formula (XIX):
The method further comprises the steps of
(b) protecting the hydroxyl group in the compound of formula (XIX) with a removable hydroxyl protecting group X; and
(c) introducing a double bond in the five-membered ring to yield a compound of the formula (XX):
wherein X is a removable hydroxyl protecting group.
The method further comprises the steps of
(d) reducing the keto group to yield a hydroxy group under conditions that yield a compound of formula (XXI):
(e) eliminating the cyclopentenol hydroxyl group;
(f) removing hydroxyl protecting group X to yield a compound of formula (XXII):
(g) oxidizing the cyclohexanol hydroxyl group to yield a compound of formula (XXIII):
The method further comprises the step of
(h) following step (d), treating the alcohol with mesyl chloride to produce
a mesylate of the formula (XXIV):
With respect to both mesylates of formulas (XVIII) and (XXIV), the mesylates are relatively unstable and convert to fulvenes upon standing. Removal of the protecting group X and oxidation yield compounds of formulas (XVII) and (XXIII), respectively.
The invention also provides novel compounds of formula I-XXIV, all of which are useful as intermediates in the synthesis of 6-substituted acylfulvene analogs (6-substituted acylfulvenes) as disclosed, for example, in Kelner et al., U.S. Pat. No. 5,523,490, or which have antitumor or cytotoxic activity per se.
FIG. 1 is a schematic representation of the synthesis of a compound of Formula (I), specifically compound 26.
FIG. 2 is a schematic representation of the synthesis of compound of Formula (XV), specifically compound 35.
FIG. 3 is a schematic representation of the synthesis of compound of Formula (XV), specifically compound 42.
An illudin analog of formula (I), where R and R′ are methyl (compound 26), can be synthesized by utilizing FIG. 1. The numbers following the named compounds refer to the numbered compounds of Schemes I, II and III. The staring compound (14) is readily prepared from furfural and methylmagnesium chloride followed by acid catalyzed rearrangement (Piancatelli et al., Tetrahedron Lett. 3555 (1976)). Protection of the hydroxyl in 14 by forming the acetal derivative 15, for example, followed by reaction with ylide 5 gives the adduct 16 (84% yield). Mild base treatment (KOH—MeOH, room temp., 1 h) of 16 affords the unsaturated ketone 17 (95%). Dihydroxylation of 17 with OsO4, NMO in THF (room temp., 24 h) gives the cis-dihydroxy product 18 which is converted to the acetonide 19 with dimethoxy propane and p-TsOH (87% for the two steps). Regioselective reaction of 19 with methylmagnesium chloride (in THF, −78° C.) affords the Grignard product 20. Treatment of 20 with 10% KOH—MeOH at 80° C. for 2 h cleaves the oxybridge giving the diol 21 (75% for the two steps). The structure (21) has been confirmed by X-ray crystallographic analysis which indicates trans relationship of the two hydroxyls.
Hydrolysis of the acetonide with Dowex resin (He form) in MEOH at room temperature for 12 h affords the tetraol 22 in 95% yield. Conversion of 22 to the orthoester 23 by treatment with trimethylorthoformate and p-TsOH at room temperature followed by heating 23 at 19° C. under reduced pressure results in elimination of the cis hydroxyls yielding the dienone. The yields in this reaction are rather low but can be improved by adding acetic anhydride. A good yield of the monoacetate and diacetate (24 a, b) is obtained. Reduction of the ketone with NaBH4—CeCl3 gives the corresponding alcohol which is unstable and is converted to the fulvene on standing. The acetate groups are removed by treatment with lithium aluminum hydride and the resulting fulvene 25 is oxidized with the Dess-Martin reagent to ±acylfulvene 26. The overall yield for the last four steps is approximately 30%.
An acylfulvene analog of formula (XV) where R′1 and R′2 together are ethylenedioxy (compound 35), may be synthesized as shown in FIG. 2. The oxybridge in the intermediate 7 is cleaved with K2CO3 in isopropanol at room temperature giving the diketone 27 (82%). Regioselective acetal formation (ethylene glycol, p-TsOH, C6H6, room temperature) gives in quantitative yield the monoacetal 28. Protection of the hydroxyl as the triethyl silyl ether (triethylsilylchloride, pyridine, 60° C.) is quantitative. A double bond is introduced into compound 29, by treatment with benzene seleninic anhydride in chlorobenzene at 95° C., yielding cross conjugated ketone 30 (78%). Reduction of 30 (NaBH4, CeCl3. 7H2O in MeOH) gives alcohol 31. This compound on treatment with methane sulfonyl chloride and triethylamine gives the fulvene 33 (via the unstable mesylate 32). Removal of the silyl protecting group (p-TsOH, acetone-water 1:1) gives the alcohol 34, which upon oxidation with pyridinium dichromate in dichloromethane affords the acylfulvene 35 (60% yield for four steps).
Another analog of formula (XVII) where R1 is OH and R2 is H (compound 42) can be made from intermediate 27. As shown in FIG. 3, compound 27 is converted to the triethylsilyl (TES) ether 36. A double bond is then introduced in the five membered ring by reaction with phenylseleninic anhydride giving 37 in good yield. Reduction of the diketone with sodium borohydride-ceric chloride gives the corresponding alcohols accompanied by rearrangement of the TES group, resulting in compound 38. Treatment of the latter with triethylamine and mesylchloride gives the unstable mesylate 39 which directly yields the fulvene 40. Oxidation of 40 with Dess-Martin reagent and removal of the silyl protecting group gives ±acylfulvene analog 42.
The compounds of formulas (I), (XVII) and (and intermdiates thereof are useful as antineoplastic agents, i.e., to inhibit tumor cell growth in vitro or in vivo, in mammalian hosts, such as humans or domestic animals, and are particularly effective against solid tumors and multi-drug resistant tumors. These compounds may be particularly useful for the treatment of solid tumors for which relatively few treatments are available. Such tumors include epidermoid and myeloid tumors, acute (AML) or chronic (CML), as well as lung, ovarian, breast and colon carcinoma. The compounds can also be used against endometrial tumors, bladder cancer, pancreatic cancer, lymphoma, Hodgkin's disease, prostate cancer, sarcomas and testicular cancer as well as against tumors of the central nervous system, such as brain tumors, neuroblastomas and hematopoietic cell cancers such as B-cell leukemia/lymphomas, myelomas, T-cell leukemia/lymphomas, and small cell leukemia/lymphomas. These leukemia/lymphomas could be either acute (ALL) or chronic (CLL).
The compounds may also be incorporated in a pharmaceutical composition, such as pharmaceutical unit dosage form, comprising an effective anti-neoplastic amount of one or more of the illudin analogs in combination with a pharmaceutically acceptable carrier.
The methods of the present invention may also be adapted to make pharmaceutically acceptable salts of compounds of formula (I), (XVII) or (XXIII). Pharmaceutically acceptable salts include, where applicable, salts such as amine acid addition salts and the mono-, di- and triphosphates of free hydroxyl groups. Amine salts include salts of inorganic and organic acids, including hydrochlorides, sulfates, phosphates, citrates, tartarates, malates, maleates, bicarbonates, and the like. Alkali metal amine or ammonium salts can be formed by reacting hydroxyaryl groups with metal hydroxides, amines or ammonium.
The compounds can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human cancer patient, in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intraperitoneal, intramuscular or subcutaneous routes.
The subject can be any mammal having a susceptible cancer, i.e., a malignant cell population or tumor. The analogs are effective on human tumors in m as well as on human tumor cell lines in vitro.
Thus, the compounds may be orally administered, for example, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell-gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
The tablets, troches, pills, capsules and the like may also contain the following: A binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, or saccharin or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially nontoxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.
The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound can be prepared in water, optionally mixed with a nontoxic surfactant Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical dosage forms suitable for injection or infusion use can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable of infusible solutions or dispersions. In all cases, the ultimate dosage form must be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersion or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, or example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
Useful dosages of compounds made according to the present methods can be determined by correlating the compounds' in vitro activity, and in vivo activity in animal models, such as murine or dog models as taught for illudin analogs such as those of U.S. Pat. Nos. 5,439,936 and 5,523,490, to activity in higher mammals, such as children and adult humans as taught, e.g., in Borch et al. (U.S. Pat. No. 4,938,949).
The therapeutically effective amount of analog necessarily varies with the subject and the tumor to be treated. However, it has been found that relatively high doses of the analogs can be administered due to the decreased toxicity compared to illudin S and M. A therapeutic amount between 30 to 112,000 μg per kg of body weight is especially effective for intravenous administration while 300 to 112,000 μg per kg of body weight is effective if administered intraperitoneally. As one skilled in the art would recognize, the amount can be varied depending on the method of administration.
The invention will be further described by reference to the following detailed examples.
Synthesis of Compound 36
Solvents were dried and distilled prior to use. THF and diethyl ether were distilled from sodium-benzophenone, CH2Cl2 and triethylamine from CaH2, Melting points are uncorrected. 1H— and 13C—NMR spectra were measured at 300 MHz and 75 MHz, respectively. High resolution mass spectra were determined at 70 ev (EI) by the Mass Spectrometry Service Laboratory at the University of Minnesota Column chromatography was performed on silica gel (Davisil 230-425 mesh, Fisher Scientific ). In some cases, a small amount of triethylamine was used to neutralize the silica gel.
To a solution of 14 (0.448 g, 4 mmol) in 2-methoxypropene (1.55 ml, 16.2 mmol), a drop of POCl3 was added under Ar. The solution was stirred at 25° C. for 12 hours and quenched by 3 drops of Et3N. The volatile components were removed in vacuo and the product 15 was obtained as a brown liquid which crystallized below 0° C. (0.69 g, 94.3%). 1H NMR (CDCl3): δ 7.43(dd, 1H), 6.17(d, 1H), 4.58(br s, 1H), 3.26(s, 3H), 2.26(m, 1H), 1.41(s, 3H), 1.40(s, 3H), 1.22(d, 3H).
To a mixture of 15 (5.02 g, 27.3 mmol), rhodium acetate (145 mg, 0.33 mmol), DMF(500 uL) in CH2Cl2(50 mL), a solution of 4 (6.0 g, 39.5 mmol) in CH2Cl2 (50 mL) was added dropwise within 10 minutes at 40° C. The orange-red solution was refluxed at 40° C. for 1.5 hours and the solvent was removed in vacuo. Chromatography (Hexane/EtOAc, 10:2) gave product 16 as white crystals (7.10 g, 84.5%). m.p.: 142-144° C.; 1H NMR (CDCl3): δ 4.98(s, 1H), 4.13(dd, 1H), 3.28(s, 3H), 2.82(t, 1H). 2.63(d, 1H), 2.54(m, 1H), 1.43(s,3H), 1.42(s,3H), 1.18(s, 3H), 1.08(d, 3H). 1.29(m, 1H), 1.03-1.16(m, 2H), 0.72(m, 1H); 13C NMR (CDCl3): δ 213.3, 212.1, 101.2, 87.4, 81.8, 73.8, 59.4, 50.4, 49.7, 45.8, 39.0, 26.0, 25.1, 14.1, 13.7, 12.4, 11.4. IR (film, cm−1): 2985, 1738, 1389, 1339, 1173, 1080, 1052, 991, 859, 827; HRMS calcd. for C17H24O5: 308.1624, found: 308.1625.
The solution of 16 (594.3mg, 1.93 mmol) in 5% KOH—MeOH (35 ml) was stirred at room temperature for 1 hour. The generated red solution was then neutralized and extracted with EtOAc. The combined organic phase was washed with sat. brine (20 ml×2) and dried over Na2SO4. Chromatography (Hexanes/EtOAc, 10:3)gave the product 17 as white crystals (390.9 mg, 93%).m.p.: 108.5-109.4C; 1H NMR (CDCl3): δ 7.15(d, 1H), 4.24(s, 1H), 3.21(br s, 1H), 2.55(d, 1H), 1.75(s, 3H), 1.23(s, 3H), 1.25(m, 1H), 1.10(m, 1H), 0.97(m, 1H), 0.74(m, 1H); 13C NMR (CDCl3): δ 211.77, 205.86, 154.23, 145.86, 86.05, 80.93, 54.68, 45.82, 37.56, 14.05, 13.22, 11.58, 10.22; IR (film, cm−1): 1754, 1703, 1639, 1389, 1339, 997; HRMS calcd. for C13H14O3: 218.0943, found: 218.0941.
To a solution of 17 (349.4 mg, 1.60 mmol), NMO (355 mg) in THF (17.7 ml) and H2O (0.5 ml), was added OsO4-THF solution (2.5wt %, 3.5 ml). After stirred at 25° C. for 21hrs, the reaction was quenched by aqueous Na2SO3 solution. The reaction mixture was extracted with EtOAc. The organic phase was washed with sat. NaCl solution, dried over Na2SO4 and concentrated. The crude diol product 18 was used for next step without further purification. A small amount of 18 was purified by chromatography. 1H NMR (CDCl3): δ 4.60(s,1H), 3.95(t, 1H), 3.01(d, 1H), 2.94(d, 1H), 2.88(s, 1H), 2.81(dd, 1H), 1.36(s, 3H), 1.28(s, 3H), 1.33(m, 1H), 1.18(m, 1H), 1.06(m, 1H), 0.75(m, 1H).
The crude diol 18 was reacted with 2,2dimethoxypropane (0.8 ml, 4eq.) in CH3CN (8.0 ml) in the presence of a trace of pTsOH. After being stirred at 25° C. for 10 hrs, the mixture was diluted with CH2Cl2 and washed with sat NaHCO3 solution and brine. Chromatography (Hexanes/EtOAc, 10:2) gave the product 19 as white crystals (308.5 mg, 87.3%). m.p.: 178.5-179.5° C.; 1H NMR (CDCl3): δ 4.58(s, 1H), 4.36(s, 1H), 2.89(q, 2H), 1.42(s, 3H), 1.34(s, 3H), 1.31(s, 3H), 1.20(s, 3H), 1.28(m, 1H), 1.16(m, 1H), 1.05(m, 1H), 0.69-0.76(m, 1H); 13C NMR (CDCl3): δ 215.53, 210.05, 110.66, 87.96, 86.44, 85.03, 83.34, 57.36, 45.37, 38.49, 27.17, 25.96, 16.92, 14.19, 13.57, 12.32; IR (film, cm−1): 2986, 1746, 1372, 1338, 1247, 1216, 1158, 1082; HRMS calcd. for C16H20O5: 292.1311, found: 292.1315.
To the solution of 19 (289.5mg, 0.99 mmol) in THF (25 ml) at −78° C., was added MeMgCl-THF solution (3.0M, 830 μl, 2.5 eq) slowly. After 2.5 hrs, the solution was warmed to 0° C. and quenched with sat. NH4Cl solution. The solution was extracted with EtOAc and the organic phase was washed with brine solution. Concentration of dried organic solution gave the crude compound 20. 1H NMR (CDCl3): δ 4.29(s, 1H), 4.23(s, 1H), 3.45(d, 1H), 2.78(d, 1H), 1.39(s, 3H), 1.35(s, 3H), 1.33(s, 3H), 1.24(s, 3H), 1.01(s, 3H), 0.77(m, 1H), 0.67(m, 1H), 0.52(m, 1H), 0.20(m, 1H); IR (film, cm−1): 3492, 2984, 2934, 1743, 1454, 1373, 1257, 1210, 1159, 1082; HRMS calcd. for C17H24O5: 308.1624, found: 308.1629.
The crude compound 20 was dissolved in 10% KOH-MeOH solution. The red mixture was heated at 80° C. for 2 hrs then partitioned between H2O and CH2Cl2. The organic layer was washed with brine then dried over Na2SO4. Chromatography (Hexanes/EtOAc, 10:15) gave the product 21 as white crystals (228.0 mg, 75%) (inseparable mixture of isomers shown by 1H NMR). m.p.: 162.0-164.0° C.; 1H NMR (CDCl3): δ 4.52(d, 1H), 3.88(dd, 1H), 3.38(m, 1H), 2.33(d, 1H), 2.18(s, 1H), 1.81(d, 3H), 1.42(s, 3H), 1.38(s, 3H), 1.07(s, 3H), 0.97-1.18(m, 4H); 13C NMR (CDCl3): δ 201.52, 152.89, 126.44, 112.96, 85.95, 81.34, 73.14, 72.31, 44.44, 29.41, 28.71, 28.22, 22.82, 21.07, 14.11, 12.58, 7.58; IR (film, cm−1): 3455, 2987, 2935, 1694, 1599, 1445, 1373, 1240, 1212, 1092, 1048; HRMS calcd for C17H24O5: 308.1624, found: 308.1624.
The compound 21 (60.9 mg, 0.20 mmol) was stirred with Dowex 50w-x16 resin (2.96 g) in MeOH (5.0 ml) at r.t. for 22 hrs. The resin was filtered away and the filtrate was washed with sat NaHCO3, sat NaCl and dried over Na2SO4. Chromatography (CH2Cl2/MeOH, 10:1) gave the product as white crystals (49.5 mg, 93%). m.p.: 149.0-151.0° C.; 1H NMR (CD3OD): δ 3.83(d, 1H), 3.81(s, 1H), 3.25(m, 1H), 1.90(d, 3H), 1.25(s, 3H), 1.07(s, 3H), 0.99-1.11(m, H); 13C NMR (CD3OD): δ 202.95, 156.24, 127.16, 76.44, 74.38, 74.12, 71.69, 4.52, 30.07, 23.14, 20.03, 14.56, 13.30, 8.20; HRMS calcd. for C14H20O5: 68.1311, found: 268.1312.
Compound 24a and 24b.
To the solution of 22 (40.2 mg, 0.15 mmol) and pTsOH (3.0 mg) in THF (3.0 ml), was added HC(OCH3)3(130 μl, 8 eq.) at 25° C. After 2 hrs, sat. NaHCO3 solution was added and the mixture was extracted with EtOAc. The combined organic phase was washed with brine and dried over Na2SO4. Concentration of the filtrate gave the ortho ester 23 (46.3 mg, 100%) as the intermediate for next reaction.
The ortho ester 23 (35.7 mg, 0.12 mmol) in Ac2O (2.0 ml) was heated at 150° C. for 1 hr. To the cooled reaction solution was added sat NaHCO3 solution and extracted with EtOAc. The organic phase was washed with brine and dried over Na2SO4. chromatography (Hexanes/EtOAc, 10:3 to 10:7) gave the products 24a and 24b as white crystals in 57.3% (18.2 mg) and 9.8% (3.6 mg) respectively.
m.p.: 119-121° C.; 1H NMR (CDCl3): δ 6.98(s, 1H), 5.25(d, 1H), 3.92(br s, 1H), 1.95(s, 3H), 1.92(s, 3H), 1.80(t, 3H), 0.94-1.42(m,4H); 13C NMR (CDCl3): δ 195.59, 170.87, 147.53, 145.85, 145.25, 128.16, 74.16, 72.64, 41.02, 30.30, 22.93, 20.89, 13.48, 11.19, 11.00, 7.70; IR (film, cm−1): 3431, 2982, 2914, 1735, 1671, 1613, 1437, 1374, 1237, 1222, 1086, 1027; HRMS calcd. for C16H20O4: 276.1362, found: 276.1363.
mp.: 1893-1912° C.; 1H NMR (CDCl3): δ 6.95(s, 1H), 6.12(d, 1H), 3.49(br s, 1H), 2.00(s, 3H), 1.97(s, 3H), 1.92(s, 3H), 1.79(s, 3H), 1.30(s, 3H), 0.92-1.27(m, 4H); 13C NMR (CDCl3): δ 195.35, 170.17, 170.35, 146.76, 146.00, 145.47, 127.95, 83.75, 70.53, 41.12, 29.27, 22.38, 20.78, 17.23, 12.35, 11.39, 10.95, 9.11.
Compound 26 Acylfulvene from 24a.
To the clear solution of 24a (2.3 mg, 8.8 umol), CeCl3.7H2O (24.9 mg, 8.0 eq) in Methanol (78 ul) and THF (155 ul) at 0° C., excess of NABH, was added in one portion After 15 minutes at 0° C., the suspenson was stirred at 25° C. for 30 minutes. At 0° C., the mixture was quenched with 5% HCl solution and Sat.NH4Cl solution and extracted with CH2Cl2. The organic phase was washed with H2O and dried over MgSO4. Concentration and chromatography (Hexanes/EtOAc, 10:5) gave the product as yellow solid (1.8 mg, 84%). 1H NMR (CDCl3): δ 6.06(s, 1H), 6.01(s, 1H), 5.84(s, 1H), 2.21(s, 3H), 2.04(s, 3H), 1.81(s, 3H), 1.15(s, 3H), 0.62-1.44(m, 4H);
The yellow compound was then dissolved in absolute ethanol (100 ul) and a trace of KCN was added. The solution was stirred overnight at 25° C. and TLC showed the compound 25 was the exclusive product. The solution was diluted with ether and washed with sat.brine and dried over Na2SO4.
After concentration, the crude diol 25 was oxidized by Dess-Martin reagent (11.8 mg) in CH2Cl2 solution (1.2 ml). After being stirred at 25° C. for 1 hour, the reaction solution was diluted with ether and quenched with the mixture of aqueous sodium bicarbonate and sodium bisulfite. The organic phase was washed with sat. NaHCO3 and sat NaCl solution and dried over NaSO4. Concentration and chromatography (Hexanes/EtOAc, 10:1) gave product 26 Acylfulvene as a yellow gum (1.1 mg, 47% from 24a). 1H NMR (CDCl3): δ 7.16(s, 1H), 6.43(t, 1H), 2.15(s, 3H), 2.00(s, 3H), 1.38(s, 3H), 0.70-1.55(m, 4H); IR (film, cm−1): 3464, 2922, 2851, 1723, 1664, 1610, 1487, 1441, 1355, 1327, 1264, 1095, 1031; HRMS calcd. for C14H16O2: 217.1229(M+H+), found: 217.1224(M+H+).
Compound 26 Acylfulvene from 24b.
To the clear solution of 24b (4.1 mg, 0.013 mmol), CeCl3.7H2O (39.5 mg, 0.11 mmol) in Methanol (100 ul) and THF(200 ul) at 0° C., excess of NABH4 was added in one portion. After 1 hour at 0° C., the suspension was stirred at 25° C. for 15 minutes. At 0° C., the mixture was quenched with 5% HCl solution and Sat.NH4Cl solution and extracted with CH2Cl2. The organic phase was washed with H2O and dried over MgSO4. Concentration and chromatography (Hexanes/EtOAc, 10:3) gave the product as yellow solid (3.9 mg, 100% ). 1H NMR (CDCl3): δ 6.24(s, 1H), 6.18(s, 1H), 6.02(d, 1H), 2.06(s, 3H), 2.03(s, 3H), 1.89(s, 3H), 1.82(s, 3H), 1.50(s, 3H), 1.39(m, 1H), 0.99-1.07(m, 3H);
The yellow solid (3.0 mg, 0.01 mmol) was redissolved in ether (0.6 ml) and added to the reaction vial with LiAlH4 (12 mg, 0.31 mmol) in ether (0.4 ml) at 0° C. The suspension was stirred at 0° C. for 30 minutes and warmed up to 25° C. for 20 minutes. The reaction was quenched with acetone then 5% HCl solution and sat NH4Cl solution were added. The mixture was extracted with ether. The combined ether phase was washed with sat. NaCl solution and dried over NaSO4. Remove of solvent gave the crude diol 25.
The crude diol 25 was oxidized by Dess-Martin reagent (70 mg) in CH2Cl2 solution (1.5 ml). After being stirred at 25° C. for 1 hour, the reaction solution was diluted with ether and quenched with the mixture of aqueous sodium bicarbonate and sodium bisulfite. The organic phase was washed with sat. NaCO3 and sat NaCl solution and dried over NaSO4. Concentration and chromatography (Hexanes/EtOAc, 10:1) gave product 26 Acylfulvene as a yellow gum (0.7 mg, 33% from 24b). 1H NMR (CDCl3): δ 7.16(s, 1H), 6.43(t, 1H), 2.15(s, 3H), 2.00(s, 3H), 1.38(s, 3H), 0.70-1.55(m, 4H); IR (film, cm−1): 3464, 2922, 2851, 1723, 1664, 1610, 1487, 1441, 1355, 1327, 1264, 1095, 1031; HRMS calcd. for C14H16O2: 217.1229 (M+H+), found: 217.1224 (M+H+).
Synthesis of Compound 35
Melting points are uncorrected. 1H and 13C NMR spectra were measured at 300 and 75 MHz. High resolution mass spectra were determined at the University of Minnesota Mass Spectrometry Service Laboratory. All chromatography used silica gel (Davisil 230-425 mesh, Fisher Scientific) and solvent was ethyl acetate and hexanes. Analytical TLC was carried out on Whatman 4420 222 silica gel plates. Reactions were routinely monitored by TLC. Yield was calculated after recycling starting materials.
Compound 7 was made following literature as a white solid: mp 134-6° C.; IR (KBr) 2993, 2952, 1757, 1743, 1454 cm−1; 1H NMR (CDCl3) δ 0.74 (m, 1H), 1.03 (m, 1H), 1.13 (m, 1H), 1.25 (s, 3H), 1.32 (m, 1H), 2.08 (m, 2H), 2.27 (m, 2H), 2.54 (d, J=7.5 Hz, 1H), 2.92(m, 1H), 4.45 (s, 1H); 13C NMR (CDCl3) δ 216.6, 211.4, 87.7, 87.4, 57.6, 41.3, 39.2, 38.3, 25.1, 14.1, 13.4, 11.9; MS m/z 206 (M+), 177, 149, 124; BRMS for C12H14O3 calcd 206.0943, found 206.0941.
To a stirred solution of 7 (2.83 g, 13.7 mmol) and 2-propanol (500 ml) was added K2CO3 (8 g, 58.0 mmol) at 25° C. The mixture was stirred for 7 days, then partitioned between EtOAc and water. The organic extract was washed with saturated NH4Cl and dried over MgSO4. Then the crude product was concentrated and chromatographed to give 1.88 g of 7 and 0.78 g of 27 (82.1%). 27 is a white solid: mp 183-5 IC; IR (KBr) 3369, 2995, 1696, 1616, 1407, 1367, 1226 cm−1; 1HNMR (CDCl3) δ 1.24 (m, 1H), 1.38 (m, 1H), 1.68 (m, 1H), 1.88 (m, 1H), 2.00 (s, 3H), 2.16 (m, 2H), 2.46 (m, 2H), 3.21 (m, 1H), 4.06 (d, J=2.7 Hz, 1H); 13C NMR (CDCl3) δ 206.1, 204.8, 147.5, 128.0, 72.0, 42.2, 39.5, 32.1, 21.7, 19.4, 18.6, 11.7; MS m/z 206 (M+), 177, 150, 147; HRMS for C12H14O3 calcd 206.0943, found 206.0944.
p-Tolunesulfonic acid (12 mg, 0.063 mmol) was added to a stirred solution of 27 (107 mg, 0.519 mmol) and ethylene glycol (3.04 g, 49 mmol) in benzene (10 ml) at 25° C. which was then stirred for 24 h. The mixture was partitioned between EtOAc and saturated NaHCO3. The combined organic layers were washed with saline, dried over MgSO4 and concentrated to an oil which was chromatographed to give 5 mg of 27 and 118 mg of 28 (95.3%) as colorless oil: IR (KBr) 3469, 2952, 2892, 1757, 1690, 1616, 1374, 1159, 1085 cm−1; 1H NMR (CDCl3) δ 1.00 (m, 3H), 1.36 (m, 1H), 1.88 (d, J=2.7 Hz, 3H), 1.96 (m, 2H), 236 (m, 2H), 3.19 (t, J=3.9 Hz, 1H), 3.78 (t, J=3.9 Hz, 1H), 4.00 (m, 4H); 13CNMR(CDCl3) δ 205.4, 148.3, 128.3, 108.9, 67.9, 65.6, 64.5, 41.9, 39.3, 26.8, 20. 8, 12.8, 11.5, 6.22; MS m/z 250 +), 221, 193, 177; HRMS for C14H18O4 calcd 250.1205, found 250.1201.
To a stirred solution of 28 (8.0 mg, 0.032 mmol) and pyridine (0.5 ml) was added TESCl (0.1 ml, 0.25 mmol) under N2. The reaction mixture was stiffed at 60° C. for 30 min and then concentrated to an oil. The crude product was purified by chromatography to give 13 mg of 29 (quantitative) as a colorless oil: IR (KBr) 2959, 2885, 1710, 1610, 1454, 1414, 1381, 1219 cm−1; 1H NMR (CDCl3) δ 0.62 (q, J=7.8 Hz, 6H), 0.94 (m, 1H), 1.28 (m, 1H), 1.83 (m, 1H), 1.87 (d, J=2 Hz, 3H), 2.35 (m, 2H), 3.13 (m, 2H), 3.75 (d, J=3.3 Hz, 1H), 4.01 (m, 4H); 13C (CDCl3) δ 205.6, 148.8, 128.8, 109.5, 69.1, 65.3, 64.7, 43.3, 39.5, 27.4, 21.5, 12.9, 11.6, 6.8, 6.5, 4.8; MS m/z 364 (M+), 336.291, 219, 161; HRMS for C20H32O4Si calcd 364.2070, found 364.2070.
A solution of 29 (13 mg, 0.0357 mmol) and phenylseleninic anhydride (13 mg, 0.0361 mmol) in chlorobenzene (0.5 ml) was stirred at 95° C. for 0.5 h under N2. The solution was then concentrated and chromatographed to give 4.9 mg of 29 and 7.0 mg of 30 (78.2%) as colorless oil: IR (KBr) 2959, 2878, 1716,1683, 1622, 1454, 1381, 1213 cm−1; 1H NMR (CDCl3) δ 0.54 (q, J=6.3 Hz, 6H), 0.89 (m, 10 H), 1.27 (m, 2H), 1.57 (m, 1H), 1.93 (m, 3H), 3.79 (s, 1H), 4.00 (m, 4H), 6.30 (dd, J=2.4, 6 Hz, 1H), 7.28 (dd, J=2.1, 6 Hz, 1H); 13C NMR (CDCl3) δ 195.9, 154.7, 146.9, 137.7, 127.5, 109.5, 69.2, 65.5, 64.6, 47.4, 28.0, 12.8, 11.1, 7.1, 6.7, 5.0; MS m/z 362 (M+), 333, 289,. 187, 159, 87; HRMS for C2H30O4Si calcd 362.1913, found 362.1919.
To the solution of 30 (20 mg, 0.055 mmol) and CeCl3.7H2O (35 mg, 0.094 mmol) in MeOH (1 ml) was added NaBH4 (excess). The mixture was stirred for 15 min at 25° C. and then more NaBH4 was added. After 15 min of stirring the mixture was partitioned between Et2O and saturated NH4Cl. The ether extract was dried over MgSO4 and concentrated to give crude product 31 as pale yellow oil.
To the solution of the above crude product 31 in CH2Cl2(1 ml) was added Et3N (20 ml, 0.143 mmol) and MsCl (20 ml, 0.258 mmol) respectively at 25° C. It was stirred for 5 min Then the mixture was partitioned between Et2O and saturated NaHCO3. The ether extract was washed by saline and dried over MgSO4. After concentration, it was chromatographed to give 33 and 34 as yellow gum.
To the solution of the above compound 33 in acetone (2 ml) and water (1 ml) was added some p-TsOH at room temperature. The mixture was set aside for 5 min and partitioned between Et2O and saturated NaHCO3. Then the ether extract was washed by saline and dried by MgSO4. After concentration and chromatography, it was mixed with the above product 34 to give 10.5 mg of 34 as yellow gum: IR (KBr) 3456, 2912, 2885, 1730, 1636, 1441, 1367 cm−1; 1H NMR (CDCl3) δ 0.75 (m, 1H), 1.10 (m, 2H), 1.24 (m, 1H), 1.88(s, 3H), 2.34 (d, J=6.9 Hz, 1H), 3.95 (m, 2H), 4.06 (m, 2H),4.68 (d, J=5.7 Hz, 1H), 6.34 (m, 1H), 6.42 (m, 2H); 13C NMR (CDCl3) δ 152.0, 139.8, 134.6, 130.5, 125.3, 117.9, 111.9, 71.3, 67.0, 66.1, 31.5, 16.4, 9.5, 6.6; MS m/z 232 (M+), 215, 189, 160, 145; HRMS for C14H16O3 calcd 232.1099, found 232.1093.
A solution of 34 (7.3 mg, 31 mmol) and pyridinium dichromate (26 mg, 69 mmol) in CH2Cl2 (1 ml) was stirred for 1 h at 25° C. The mixture was diluted by Et2O and then filtered. The concentrated crude product was chromatographed to give 5.2 mg of 35 (71.9%) as yellow crystal: mp 138-140° C.; IR (KBr) 2959, 2892, 1683, 1616, 1549, 1441, 1360 cm−1; 1H NMR (CDCl3) δ 1.14 (m, 2H), 1.35 (m, 2H), 2.06 (s, 3H), 4.02 (m, 2H), 4.16 (m, 2H), 6.63 (dd, J=2.4,4.8 Hz, 1H), 6.76(d, J=4.8 Hz, 1H), 7.39 (s, 1H); 13C NMR (CDCl3) δ 187.6, 159.6, 140.3, 135.4, 131.0, 127.9, 124.8, 106.2, 66.0, 33.4, 16.9, 12.9; MS m/z 230 (M+), 202,158; HRMS for C14H14O3 calcd 230.0942, found 230.0948; U γmax (methanol) 230 nm (e 6543), 330 (e 3484).
Synthesis of Compound 42
To a solution of 27 (Example II) (37 mg, 0.18 mmol) in pyridine (3 ml) was added TESCl (0.25 ml, 0.624 mmol). The mixture was stirred at 60° C. for 0.5 h under N2. After concentration and chromatography, it gave 50 rag of 36 (87%) as colorless oil: IR (KBr) 2952, 2872, 1703, 1622, 1461, 1414, 1226 cm−1; 1H NMR (CDCl3) δ 0.58 (q, J=7.8 Hz, 6H),0.97 (m, ; 10H), 1.25 (n, 2H), 1.58 (n, 1H), 1.85 (m, 2H), 1.98 (s, 3H), 2.42 (m, 2H), 3.09 (b, 1H), 4.01 (d, J=3 Hz, 1H); 13C NMR (CDCl3) 6206.0, 205.0, 147.0, 128.6, 72.6, 43.0, 39.6, 32.1, 21.4, 19.6, 18.0, 11.5, 6.5, 4.5; MS m/z 320 (M+), 291, 259, HRMS for C18H28O3Si calcd 320.1808, found 320.1803.
The solution of 36 (278 mg, 0.869 mmol) and phenylseleninic anhydride (320 mg, 0.889 mmol) in chlorobenzene (2.5 ml) was stirred at 95° C. for 0.5 h under N2. The mixture was then concentrated and chromatographed to give 58.7 mg of 36 and 131.2 mg of 37 (60.2%) as colorless gum: IR (KBr) 2952, 2878, 1730, 1690, 1636, 1454, 1240 cm−1; 1H NMR (CDCl3) δ 0.52 (q, J=7.8 Hz, 6H), 0.85 (t, J=7.8 Hz, 9H), 1.20 (m, 1H), 1.36 (m, 1H), 1.69 (m, 1H), 1.82 (m, 1H), 2.06 (s, 3H), 3.58 (s, 1H), 4.26 (d, J=2.4 Hz, 1H), 6.45 (dd, J=2.1, 6 Hz, 1H), 7.33 (dd, J=2.1, 6 Hz, 1H); 13C NMR (CDCl3) δ 205.9, 195.3, 153.2, 144.3, 139.4, 127.7, 72.1, 47.3,32.4, 20.1, 19.7, 11.4, 6.4, 4.4; MS m/z 318 (M+), 289, 261; HRMS for C18H26O3Si calcd 318.1651, found 318.1658.
To a solution of 37 (9.5 mg, 0.0299 mmol), CeCl3.7H2O (58.5 mg, 0.157 mmol) in MeOH (0.3 ml) was added NaBH4 (excess) at 25° C. It was stirred for 30 min. Then the mixture was partitioned between Et2O and saturated NH4Cl. The ether extract was dried by MgSO4 and concentrated to give crude product 38 as pale yellow oil.
To the solution of above 38 in CH2Cl2. (0.2 ml) was added Et3N (5 ml, 0.036 mmol) and MsCl (5 ml, 0.965 mmol) at 25° C. The mixture was stirred for 5 min and then separated between Et2O and saturated NaHCO3. Then the ether extract was washed by saline and dried by MgSO4. After concentration, it was chromatographed to give 8.2 mg of 40 (90.3%) as yellow gum: IR (KBr) 3557, 3449, 2946, 2878, 1716, 1643, 1461, 1112 cm−1; 1H NMR (CDCl3) δ 0.66 (q, J=7.8 Hz, 6H), 0.87 (m, 2H), 0.98 (t, J=7.8 Hz, 9H), 1.26 (m, 2H), 1.86 (s, 3H), 2.55 (d, J=3.9 Hz, 1H), 3.24 (s, 1H), 4.94 (d, J=2.1 Hz, 1H), 6.35 (m, 2H),. 6.46 (m, 1H); 13C NMR (CDCl3) δ 148.9, 140.0, 130.4, 117.8, 117.5, 77.0,68.6, 61.9, 16.1,11.6, 7.8, 6.8, 5.0; MS m/z 304 (Mt), 287, 275; HRMS for C18H28O2Si calcd 304.1859, found 304.1860.
A solution of 40 (1.2 mg, 3.95 mmol) and Dess-Martin reagent (2.2 mg, 5.19 mmol) in CH2Cl2 (0.2 ml) was stirred for 30 min at 25° C. The mixture was separated between Et2O and 10% Na2SO3. Then the ether extract was washed by saline and dried by MgSO4. After concentration, it was chromatographed to give 1.1 mg of 41 (92.3%) as yellow gum: IR (KBr) 2952, 2872, 1690, 1610, 1549, 1354, 1132 cm−1; 1H NMR (CDCl3) δ 0.71 (q, J=7.8 Hz, 6H), 0.85 (m, 1H), 0.97 (t, J=7.8 Hz, 9H), 1.21 (m, 2H), 1.45 (m, 1H), 2.08 (s, 3H), 4.50 (s, 1H), 6.66 (dd, J=2.4. 4.8 Hz, 1H), 6.72 (d, J=5.1 Hz, 1H), 7.25 (s, 1H); 13C NMR (CDCl3) δ 193.3. 161.2. 140.7, 131.8, 131.2, 128.3, 122.8, 32.9, 17.1, 12.5, 10.3, 6.9, 5.2; MS m/z 302 (M+), 273, 245; HRMS for C18H26O2Si calcd 302.1702, found 302.1710; UV γmax227 nm(e 15612), 323 nm (e 10720).
To a solution of 41 (9.0 mg, 0.0298 mmol) in acetone (0.8 ml) and H2O (0.4 ml) was added some p-TsOH. The mixture was stirred for 30 min. Then it was partitioned between Et2O and saturated NaHCO3. The ether extract was washed by saline and dried by MgSO4 After concentration, it was chromatographed to give quantitative 42 as yellow gum: IR (KBr) 3449, 3013, 2925, 1663, 1609, 1441, 1367, 1260 cm−1; 1H NMR (CDCl3) δ 0.81 (m, 1H), 1.25 (m, 1H), 1.36 (m, 1H), 1.44 (m, 1H), 2.12 (s, 3H), 3.82 (d, J=2.4 Hz, 1H), 4.55 (d, J=2.1 Hz, 1H), 6.70 (dd, J=2.7, 5.1 Hz, 1H), 6.81 (t, 1H), 7.32 (s, 1H); 13C NMR (CDCl3) δ 194.2, 162.2, 140.9, 132.7, 131.4, 126.5, 124.1, 74.6, 32.8, 17.0, 12.7, 10.3; MS m/z 188 (M+), 160, 145; HRMS for C12H12O2 calcd 188.0837, found 188.0840; UV γmax(methanol) 227 nm (e 13626), 323 nm (e 7474).
The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US4559157||21 Apr 1983||17 Dec 1985||Creative Products Resource Associates, Ltd.||Cosmetic applicator useful for skin moisturizing|
|US4608392||28 Aug 1984||26 Aug 1986||Societe Anonyme Dite: L'oreal||Method for producing a non greasy protective and emollient film on the skin|
|US4612302||14 Nov 1983||16 Sep 1986||Brigham And Women's Hospital||Clinical use of somatostatin analogues|
|US4684620||4 Sep 1984||4 Aug 1987||Gibson-Stephens Neuropharmaceuticals, Inc.||Cyclic polypeptides having mu-receptor specificity|
|US4820508||23 Jun 1987||11 Apr 1989||Neutrogena Corporation||Skin protective composition|
|US4853371||22 Jun 1988||1 Aug 1989||The Administrators Of The Tulane Educational Fund||Therapeutic somatostatin analogs|
|US4938949||12 Sep 1988||3 Jul 1990||University Of New York||Treatment of damaged bone marrow and dosage units therefor|
|US4992478||4 Apr 1988||12 Feb 1991||Warner-Lambert Company||Antiinflammatory skin moisturizing composition and method of preparing same|
|US5387578||1 Aug 1991||7 Feb 1995||Farmitalia Carlo Erba S.R.L.||New linker for bioactive agents|
|US5439936||9 Feb 1993||8 Aug 1995||The Regents Of The University Of California||Method of treating certain tumors using illudin analogs|
|US5439942||31 Oct 1990||8 Aug 1995||The Regents Of The University Of California||Method of treating certain tumors using illudin analogs|
|US5523490||1 Nov 1994||4 Jun 1996||The Regents Of The University Of California||Illudin analogs|
|US5563176||15 Jul 1994||8 Oct 1996||The Regents Of The University Of California||Illudin analogs useful as antitumor agents|
|US5723632||8 Aug 1996||3 Mar 1998||Mgi Pharma, Inc.||Total synthesis of antitumor acylfulvenes|
|US5932553||18 Jul 1996||3 Aug 1999||The Regents Of The University Of California||Illudin analogs useful as antitumor agents|
|US6025328||20 Feb 1998||15 Feb 2000||The Regents Of The University Of California||Antitumor agents|
|JPS62234040A||Title not available|
|WO1991004754A2||2 Oct 1990||18 Apr 1991||The Regents Of The University Of California||Illudin analogs as anti-tumor agents|
|WO1994018151A1||2 Feb 1994||18 Aug 1994||The Regents Of The University Of California||Acylfulvene analogues as antitumor agents|
|WO1994025013A1||26 Apr 1994||10 Nov 1994||Smithkline Beecham Corporation||Endothelin receptor antagonists|
|WO1996034005A1||26 Apr 1996||31 Oct 1996||Sloan-Kettering Institute For Cancer Research||Synthesis of the breast tumor-associated antigen defined by monoclonal antibody mbr1 and uses thereof|
|WO1997003995A1||24 Jul 1996||6 Feb 1997||Sloan-Kettering Institute For Cancer Research||Synthesis of glycoconjugates of the lewis y epitope and uses thereof|
|WO1998003458A1||14 Jul 1997||29 Jan 1998||The Regents Of The University Of California||Illudin analogs useful as antitumor agents|
|1||Anchel, M., et al., "Antibiotic Substances From Basidiomycetes. VII. Clitocybe Illudens", Proceedings of the National Academy of Sciences, 36 (5), pp. 300-305, (1950).|
|2||Anchel, M., et al., "The Biogenesis of Illudins S and M in Clitocybe Illudens", Phytochemistry, 9 (11), pp. 2339-2343, (Nov. 1970).|
|3||Arap, W., et al., "Cancer Treatment by Targeted Drug Delivery to Tumor Vasculature in a Mouse Model", Science, 279, pp. 377-380, (Jan. 16, 1998).|
|4||Brandsteterova, E., et al., "HPLC Analysis of Novel Anti-Cancer Agents-Illudens and Their Analogs", Journal of Liquid Chromatography, 16 (1), pp. 115-125, (1993).|
|5||Brandsteterova, E., et al., "HPLC Determination of a New Anticancer Agent (Acylfulvene) in Serum", Neoplasma, 39 (6), pp. 369-373, (1992).|
|6||Burres, N.S., et al., "Antitumor Activity and Mechanism of Action of the Novel Marine Natural Products Mycalamide-A and -B and Onnamide", Cancer Research, 49, pp. 2935-2940, (Jun., 1989).|
|7||Curtis, E.A., et al., "An Efficient Dipolar-Cycloaddition Route to the Pterosin Family of Sesquiterpenes", Tetrahedron Letters, 36 (12), pp. 1989-1992, (Mar. 1995).|
|8||Dillman, R.O., et al., "Athymic Mouse Model of a Human T-Cell Tumor", Cancer Research, 45, pp. 5632-5636, (Nov., 1985).|
|9||Eva, K.M., et al., "An Efficient Sythesis of Pterosin C and Other Pterosins", Canadian Journal of Chemistry, 62 (10), pp. 1945-1953, (Oct. 1984).|
|10||French, A.L., et al., "Poisoning with the North American Jack O'Lantern Mushroom", Clinical Toxicology, 26 (1 & 2), pp. 81-88, (1988).|
|11||Giovanella, B.C., et al., "Correlation Between Response to Chemotherapy of Human Tumors in Patients and in Nude Mice", Cancer, 52, pp. 1146-1152, (1983).|
|12||Giovanella, B.C., et al., "DNA Topoisomerase I-Targeted Chemotherapy of Human Colon Cancer in Xenografts", Science, 246 (4933), pp. 1046-1048, (Nov. 24, 1989).|
|13||Goldin, A., et al., "Current Results of the Screening Program at the Division of Cancer treatment, National Cancer Institute", Europ. J. Cancer, 17, pp. 129-142, (1981).|
|14||Goldin, A., et al., "Historical Development and Current Strategy of the National Cancer Institute Drug Development Program", In: Methods in Cancer Research, vol. XVI, Cancer Drug Development Part A, Chapter V, Academic Press, Inc., New York, pp. 165-245, (1979).|
|15||Greene, T.W., Protective Groups in Organic Synthesis, Chapters 4, 5 & 6, John Wiley & Sons, Inc., New York, pp. 114-217, (1981).|
|16||Hanson, J.R., et al., "Studies in Terpenoid Biosynthesis. Part XV. Biosynthesis of the Sesquiterpenoid Illuden M", Journal of the Chemical Society, Perkin Transactions I, pp. 876-880, (1976).|
|17||Hara, M., et al., "6-Deoxyilludin M, a New Antitumor Antibiotic: Fermentation, Isolation and Structural Identification", The Journal of Antibiotics, 40, pp. 1643-1646, (Nov. 1987).|
|18||Harttig, U., et al., "Leaianafulvene, a Sesquiterpenoid Fulvene Derivative from Cultures of Mycena Leaiana", Phytochemistry, 29 (12), pp. 3942-3944, (1990).|
|19||Hirono, I., et al., "Repreoduction of Acute Bracken Poisoning in a Calf with Ptaquiloside, a Bracken Constituent", The Veterinary Record, 115 (15), pp. 375-378, (Oct. 1984).|
|20||Inoue, K., et al., "Antitumor Efficacy of Seventeen Anticancer Drugs in Human Breast Cancer Xenograft (MX-1) Transplanted in Nude Mice", Cancer Chemother. Pharmacol., 10, pp. 182-186, (1983).|
|21||Kawato, Y., et al., "Antitumor Activity of a Camptothecin Derivative, CPT-11, Against Human Tumor Xenografts in Nude Mice", Cancer Chemother. Pharmacol., 28, pp. 192-198, (1991).|
|22||Kelner, M.J., et al., "In Vitro and In Vivo Studies on the Anticancer Activity of Dehydroilluden M", Anticancer Research, 15, pp. 873-878, (1995).|
|23||Kelner, M.J., et al., "Nonresponsiveness of the Metastatic Human Lung Carcinoma MV522 Xenograft to Conventional Anticancer Agents", Anticancer Research, 15, pp. 867-872, (1995).|
|24||Kelner, M.J., et al., "Preclinical Evaluation of Illudens as Anticancer Agents", Cancer Research, 47, pp. 3186-3189, (1987).|
|25||Kelner, M.J., et al., "Preclinical Evaluation of Illudens as Anticancer Agents: Basis for Selective Cytotoxicity", J. Natl. Cancer Inst., 82 (19), pp. 1562-1565, (1987).|
|26||Lu, J., et al., "An expeditious synthesis of the potent antitumor agent, (+)-hydroxymethylacylfulvene using an allenic Paulson-Khand type cycloaddition", American Chemical Society, Division of Organic Chemistry Abstracts, 217th ACS National Meeting in Anaheim, CA, 1 p., (Mar. 21-25, 1999).|
|27||Matsumoto, T., et al., "An Alternative Synthesis of Illudin M", Tetrahedron Letters, 14, pp. 1171-1174, (Mar. 1970).|
|28||Matsumoto, T., et al., "Synthesis of Illudin S", Tetrahedron Letters, 23, pp. 2049-2052, (May 1971).|
|29||McMorris, T.C., et al., "(Hydroxymethyl) Acyfulvene: An Illuden Derivative with Superior Antitumor Properties", Journal of Natural Products, 59 (9), pp. 896-899, (Sep. 1996).|
|30||McMorris, T.C., et al., "Acylfulvenes, a New Class of Potent Antitumor Agents", Experientia, 52 (1), pp. 75-80, (Apr. 21, 1995).|
|31||McMorris, T.C., et al., "An Acetal Derivative of Illudin S with Improved Antitumor Activity", Tetrahedron letters, 38 (10), pp. 1697-1698, (1997).|
|32||McMorris, T.C., et al., "Design and Synthesis of Antitumor Acylfulvenes", The Journal of Organic Chemistry 62 (9), pp. 3015-3018, (1997).|
|33||McMorris, T.C., et al., "Fungal Metabolites. The Structures of the Novel Sesquiterpenoids Illudin -S and -M", J. of Amer. Chem. Soc., 87 (7), pp. 1594-1600, (1965).|
|34||McMorris, T.C., et al., "On the Mechanism of Toxicity of Illudens: The Role of Glutathione", Chemical Research Toxicology, 3 (6), pp. 574-579, (Nov./Dec. 1990).|
|35||McMorris, T.C., et al., "Reaction of Antitumor Hydroxymethylacylfulvene (HMAF) with Thiols", Tetrahedron, 53 (43), pp. 14579-14590, (1997).|
|36||McMorris, T.C., et al., "Structure and reactivity of Illudens", Tetrahedron, 45 (17), pp. 5433-5440, (1989).|
|37||McMorris, T.C., et al., "Structure-Activity Relationships of Illudens: Analogs with Improved Therapeutic Index", Journal of Organic Chemistry, 57 (25), pp. 6876-6883, (Dec. 4, 1992).|
|38||McMorris, T.C., et al., "Total Synthesis of hydroxymethylacylfulvene, an antitumour derivative of illudin S", Chem. Commun., pp. 315-316, (1997).|
|39||Padwa, A., et al., "An approach toward the Illudin family of sesquiterpenes using the tandem cyclization-cycloaddition reaction of rhodium carbenoids", The Journal of Organic Chemistry, 62 (5), pp. 1317-1325, (Mar. 7, 1997).|
|40||Padwa, A., et al., "Generation and Cycloaddition behavior of spirocyclic carbonyl ylides. Application to the synthesis of the Pterosin Family of Sequiterpenes", The Journal of Organic Chemistry, 61 (1), pp. 73-81, (Jan. 12, 1996).|
|41||Padwa, A., et al., "Synthetic studies toward Illudins and Ptaguilosin. A Highly Convergent approach via the dipolar cycloaddition of carbonyl ylides", The Journal of the American Chemical Society, 116, pp. 2667-2668, (1994).|
|42||Schabel, F.M., et al., "Testing Therapeutic Hypotheses in Mice and Man:Observations on the Therapeutic Activity Against Advanced Solid Tumors of Mice Treated with Anticancer Drugs that Have Demonstrated or Potential Clinical Utility for Treatment of Advanced Solid Tumors of Man", In: Methods in Cancer Research, vol. XVII, Cancer Drug Development Part B, Chapter 1, Academic Press, Inc., pp. 3-50, (1979).|
|43||Shimomura, O., "The Role of Superoxide Dismutase in Regulating the Light Emission of Luminescent Fungi", The Journal of Experimental Botany, 43, (256), pp. 1519-1525, (Nov. 1992).|
|44||Shinozawa, S., et al., "The Antitumor Effect of Illudin S (Lampterol) Entrapped in Liposome for Mice Inolculated with Ehrlich Ascites Tumor Cells", Chemical Abstracts, 90 (25), Abstract No. 197682m, 1 p., (Jun. 18, 1979).|
|45||Steel, G.G., et al., "The Response to Chemotherapy of a Variety of Human Tumor Xenografts", Br. J. Cancer, 47, pp. 001-013, (1983).|
|46||Tanaka, K., et al., "Metabolism by Rat Liver Cytosol of Illuden S, a Toxic Substance of Lampteromyces Japonicus. II. Characterization of Illuden S-Metabolizing Enzyme", Xenobiotica, 22 (1),, pp. 33-39, (1992).|
|47||Tanaka, K., et al., "Metabolism of Illuden S, a Toxic Principle of Lampteromyces Japonicus, by Rat Liver. I. Isolation and Identification of Cyclopropane Ring-Cleavage Metabolites", Xenobiotica, 20 (7), pp. 671-681, (1990).|
|48||Tanaka, K., et al., "Michael-type addition of illudin S, a toxic substance from Lampteromyces japonicus with Cysteine and Cysteine-containing peptides in vitro", Chem. Pharm. Bull., vol. 44, No. 2, pp. 273-279, (1996).|
|49||Varki, N.M., et al., "Cloned Low Metastic Variants from Human Lung Carcinoma Metastases", Anticancer Research, 10, pp. 637-644, (1990).|
|50||Vendetti, J.M., et al., "Current NCI Preclinical Antitumor Screening in Vivo: Results of Tumor Panel Screening, 1976-1982, and Future Directions", Advances in Pharmacology and Chemotherapy, 20, pp. 1-20, (1984).|
|51||Venditti, J.M., "The National Cancer Institute Antitumor Drug Discovery Program, Current and Future Perspectives: A Commentary", Cancer Treatment Reports, 67 (9), pp. 767-772, (Sep. 1983).|
|52||Walser, J., et al., "Mode of Action of Illuden S", Antimicrobial Agents and Chemotherapy, 3 (3), pp. 357-363, (Mar. 1973).|
|53||Weinreb, S.M., "Fulvenes Derived from Illuden S", Tetrahedron Letters, 38, pp. 3489-3491, (Sep. 1971).|
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|International Classification||A61P35/00, C07C45/29, C07C49/737, C07C49/633, C07C35/37, A61K31/335, C07D493/08, C07C49/733|
|Cooperative Classification||Y02P20/582, Y02P20/55, C07D493/08, C07C2103/94, C07C35/37, C07C49/737|
|European Classification||C07C49/737, C07C35/37, C07D493/08|
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